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Gene Review

FKBP1A  -  FK506 binding protein 1A, 12kDa

Homo sapiens

Synonyms: 12 kDa FK506-binding protein, 12 kDa FKBP, Calstabin-1, FK506-binding protein 1A, FKBP-12, ...
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Disease relevance of FKBP1A

  • FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models, showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases [1].
  • In the context of the high expression of FKBP38 in neuroblastoma cells, these data suggest that FKBP38.CaM/Ca(2+) inhibition can mediate neurotrophic properties of FKBP ligands [1].
  • This effect was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP [2].
  • The human FKBP cDNA sequence shows significant similarity to an open reading frame in the Neisseria meningitidis genome [3].
  • They further suggest a pathophysiological role for FKBP12 as a mediator in immediate or type I hypersensitivity and may have implications for novel therapeutic strategies in the treatment of allergic disorders with FK506 and rapamycin [4].

Psychiatry related information on FKBP1A


High impact information on FKBP1A

  • This procedure involves coexpressing an FKBP-tagged Golgi enzyme with an ER-retained protein fused to FRAP in COS cells [6].
  • FKBP12 binds to the GS region of the receptor, capping the TbetaR-II phosphorylation sites and further stabilizing the inactive conformation of TbetaR-I [7].
  • Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12 [7].
  • The crystal structure of a fragment of unphosphorylated TbetaR-I, containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12 [7].
  • The human rotamase or peptidyl-prolyl cis-trans isomerase Pin1 is a conserved mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle [8].

Chemical compound and disease context of FKBP1A


Biological context of FKBP1A


Anatomical context of FKBP1A


Associations of FKBP1A with chemical compounds

  • In vitro chloroplast import of precursors of other chloroplast proteins was unaffected by concentrations of cyclosporin A which completely inhibit rotamase activity of chloroplast stromal CyP [17].
  • We now show that substitution of a Gly, Glu, or Ile for Val2461 in RyR1 prevents FKBP12 binding to RyR1, resulting in channels with increased gating frequency [15].
  • Substitution of Val(2322) for leucine (as in IP(3)R1) or isoleucine (as in RyR2) decreased the binding efficiency and shifted the selectivity to FKBP12.6; substitution of Val(2322) for aspartate completely abolished the FKBP interaction [22].
  • Energetic and structural analysis of the role of tryptophan 59 in FKBP12 [23].
  • This FK506-FKBP complex inhibits the activity of the serine/threonine protein phosphatase 2B (calcineurin), the basis for the immunosuppressant action of FK506 [20].

Physical interactions of FKBP1A

  • FKBP12 binding modulates ryanodine receptor channel gating [15].
  • FKBP6 shows homology to the FK-506 binding protein (FKBP) class of immunophilins [24].
  • A simple model system based on the effect of FK 506 on isolated rat pancreatic islets was utilised to study the relationship between inhibition of insulin biosynthesis, inhibition of interleukin 2 (IL-2) activation and FK binding protein (FKBP-12) binding of FK 506 and a number of FK 506 analogues [25].
  • Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity [26].
  • More specifically, we find that amino acids 400-420 play a critical role for Hsp90 binding by either FKBP [27].

Regulatory relationships of FKBP1A

  • There was negligible hRyR2-induced subcellular redistribution of FKBP12 [28].
  • The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP [29].
  • Whereas FKBP12 inhibited EGF receptor tyrosine kinase activity in a concentration-dependent manner, the cyclophilins did not affect autophosphorylation [30].
  • Finally, we demonstrate that FK506 and fluconazole have synergistic activity that is independent of both FKBP12 and calcineurin and may involve the known ability of FK506 to inhibit multidrug resistance pumps, which are known to export azoles from fungal cells [31].
  • The FKBP12 expression increased during ATRA-induced differentiation and expression of cyclophilin A remained unchanged [32].

Other interactions of FKBP1A

  • Whereas the binding of calcineurin to FKBP12 is potentiated by FK506, the specific association of PAHX and FKBP52 is maintained in the presence of FK506 [33].
  • Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13 [34].
  • FAP48 was identified and cloned thanks to its interaction with FK506-binding proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of immunophilins that bind the macrolide immunosuppressant drugs FK506 and rapamycin [35].
  • For both RyRs, the stoichiometry is 4 FKBP/RyR [36].
  • These molecular data are in agreement with the lack of correlation between FKBP12 and IP3R1 expression in various cell types [37].

Analytical, diagnostic and therapeutic context of FKBP1A

  • Moreover, only a small fraction of the cellular pool of the major forms of cyclophilin or FKBP needs to be occupied by the drugs in order to achieve maximal immunosuppression [38].
  • Moreover, immunoprecipitation experiments indicated a high-affinity interaction of FKBP12 with RyR1 but not with IP3R1 [37].
  • The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography [39].
  • In the course of protein engineering studies on human FKBP, we discovered that a single point mutation in the ligand-binding site (Phe-36 --> Met) converts the normally monomeric protein into a ligand-reversible dimer [40].
  • In Northern blot analysis, mRNA species of approximately 1.8 kilobases that hybridized with human FKBP cDNA were detected in poly(A)+ RNAs from brain, lung, liver, and placental cells and leukocytes [41].


  1. The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. Edlich, F., Weiwad, M., Wildemann, D., Jarczowski, F., Kilka, S., Moutty, M.C., Jahreis, G., Lücke, C., Schmidt, W., Striggow, F., Fischer, G. J. Biol. Chem. (2006) [Pubmed]
  2. The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy. Gerard, M., Debyser, Z., Desender, L., Kahle, P.J., Baert, J., Baekelandt, V., Engelborghs, Y. FASEB J. (2006) [Pubmed]
  3. Molecular cloning and overexpression of the human FK506-binding protein FKBP. Standaert, R.F., Galat, A., Verdine, G.L., Schreiber, S.L. Nature (1990) [Pubmed]
  4. Activation of Ca2+ signaling in neutrophils by the mast cell-released immunophilin FKBP12. Bang, H., Müller, W., Hans, M., Brune, K., Swandulla, D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  5. Nucleotide sequence analysis of the binding site on the inositol 1,4,5-trisphosphate type-1 receptor in bipolar disorder -- a negative study. Fujimaki, K., Morinobu, S., Takahashi, J., Yamawaki, S., Kato, N., Kanno, M., Okuyama, N., Kawakatsu, S., Otani, K., Kusumi, I., Koyama, T. Journal of affective disorders. (2001) [Pubmed]
  6. Golgi membranes remain segregated from the endoplasmic reticulum during mitosis in mammalian cells. Pecot, M.Y., Malhotra, V. Cell (2004) [Pubmed]
  7. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12. Huse, M., Chen, Y.G., Massagué, J., Kuriyan, J. Cell (1999) [Pubmed]
  8. Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Ranganathan, R., Lu, K.P., Hunter, T., Noel, J.P. Cell (1997) [Pubmed]
  9. Peptidyl-prolyl cis-trans isomerase of Bacillus subtilis: identification of residues involved in cyclosporin A affinity and catalytic efficiency. Göthel, S.F., Herrler, M., Marahiel, M.A. Biochemistry (1996) [Pubmed]
  10. Treatment of normal skeletal muscle with FK506 or rapamycin results in halothane-induced muscle contracture. Brooksbank, R.L., Badenhorst, M.E., Isaacs, H., Savage, N. Anesthesiology (1998) [Pubmed]
  11. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Heitman, J., Movva, N.R., Hall, M.N. Science (1991) [Pubmed]
  12. An FKBP12 binding assay based upon biotinylated FKBP12. Carreras, C.W., Fu, H., Santi, D.V. Anal. Biochem. (2001) [Pubmed]
  13. An immunophilin that binds M(r) 90,000 heat shock protein: main structural features of a mammalian p59 protein. Callebaut, I., Renoir, J.M., Lebeau, M.C., Massol, N., Burny, A., Baulieu, E.E., Mornon, J.P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  14. Rapamycin sensitivity in Saccharomyces cerevisiae is mediated by a peptidyl-prolyl cis-trans isomerase related to human FK506-binding protein. Koltin, Y., Faucette, L., Bergsma, D.J., Levy, M.A., Cafferkey, R., Koser, P.L., Johnson, R.K., Livi, G.P. Mol. Cell. Biol. (1991) [Pubmed]
  15. FKBP12 binding modulates ryanodine receptor channel gating. Gaburjakova, M., Gaburjakova, J., Reiken, S., Huang, F., Marx, S.O., Rosemblit, N., Marks, A.R. J. Biol. Chem. (2001) [Pubmed]
  16. Dysregulated ryanodine receptors mediate cellular toxicity: restoration of normal phenotype by FKBP12.6. George, C.H., Higgs, G.V., Mackrill, J.J., Lai, F.A. J. Biol. Chem. (2003) [Pubmed]
  17. Cloning and characterization of chloroplast and cytosolic forms of cyclophilin from Arabidopsis thaliana. Lippuner, V., Chou, I.T., Scott, S.V., Ettinger, W.F., Theg, S.M., Gasser, C.S. J. Biol. Chem. (1994) [Pubmed]
  18. cDNA cloning of a putative protochordate FK506-binding protein. Pancer, Z., Gershon, H., Rinkevich, B. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  19. FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Jeyakumar, L.H., Ballester, L., Cheng, D.S., McIntyre, J.O., Chang, P., Olivey, H.E., Rollins-Smith, L., Barnett, J.V., Murray, K., Xin, H.B., Fleischer, S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  20. FK506 and the role of immunophilins in nerve regeneration. Gold, B.G. Mol. Neurobiol. (1997) [Pubmed]
  21. Expression of FKBP12 and ryanodine receptors (RyRs) in the spinal cord of MND patients. Kihira, T., Utunomiya, H., Kondo, T. Amyotroph. Lateral Scler. Other Motor Neuron Disord. (2005) [Pubmed]
  22. The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different. Bultynck, G., Rossi, D., Callewaert, G., Missiaen, L., Sorrentino, V., Parys, J.B., De Smedt, H. J. Biol. Chem. (2001) [Pubmed]
  23. Energetic and structural analysis of the role of tryptophan 59 in FKBP12. Fulton, K.F., Jackson, S.E., Buckle, A.M. Biochemistry (2003) [Pubmed]
  24. A novel human gene FKBP6 is deleted in Williams syndrome. Meng, X., Lu, X., Morris, C.A., Keating, M.T. Genomics (1998) [Pubmed]
  25. Pancreatic and nephrotoxicity of immunomodulator compounds. Hammond, T.G., Kind, C.N. Toxicol. Lett. (1995) [Pubmed]
  26. Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity. Yang, W.M., Inouye, C.J., Seto, E. J. Biol. Chem. (1995) [Pubmed]
  27. C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and FKBP52 cause differential binding to Hsp90. Cheung-Flynn, J., Roberts, P.J., Riggs, D.L., Smith, D.F. J. Biol. Chem. (2003) [Pubmed]
  28. In situ modulation of the human cardiac ryanodine receptor (hRyR2) by FKBP12.6. George, C.H., Sorathia, R., Bertrand, B.M., Lai, F.A. Biochem. J. (2003) [Pubmed]
  29. Intracellular calcium-release channels: regulators of cell life and death. Marks, A.R. Am. J. Physiol. (1997) [Pubmed]
  30. Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal growth factor receptor. Lopez-Ilasaca, M., Schiene, C., Küllertz, G., Tradler, T., Fischer, G., Wetzker, R. J. Biol. Chem. (1998) [Pubmed]
  31. Synergistic antifungal activities of bafilomycin A(1), fluconazole, and the pneumocandin MK-0991/caspofungin acetate (L-743,873) with calcineurin inhibitors FK506 and L-685,818 against Cryptococcus neoformans. Del Poeta, M., Cruz, M.C., Cardenas, M.E., Perfect, J.R., Heitman, J. Antimicrob. Agents Chemother. (2000) [Pubmed]
  32. Possible involvement of calcineurin in retinoic acid-induced inhibition of leukemic HL-60 cell proliferation. Kihira, H., Hiasa, A., Yamamoto, M., Katayama, N., Kuno, T., Ohtsuka, K., Shiku, H., Nishikawa, M. Int. J. Oncol. (1998) [Pubmed]
  33. Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein. Chambraud, B., Radanyi, C., Camonis, J.H., Rajkowski, K., Schumacher, M., Baulieu, E.E. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  34. Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13. Jin, Y.J., Albers, M.W., Lane, W.S., Bierer, B.E., Schreiber, S.L., Burakoff, S.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  35. The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis. Krummrei, U., Baulieu, E.E., Chambraud, B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  36. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. Xin, H.B., Rogers, K., Qi, Y., Kanematsu, T., Fleischer, S. J. Biol. Chem. (1999) [Pubmed]
  37. Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)-binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor. Bultynck, G., De Smet, P., Rossi, D., Callewaert, G., Missiaen, L., Sorrentino, V., De Smedt, H., Parys, J.B. Biochem. J. (2001) [Pubmed]
  38. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Sigal, N.H., Dumont, F.J. Annu. Rev. Immunol. (1992) [Pubmed]
  39. Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. Van Duyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L., Clardy, J. Science (1991) [Pubmed]
  40. A ligand-reversible dimerization system for controlling protein-protein interactions. Rollins, C.T., Rivera, V.M., Woolfson, D.N., Keenan, T., Hatada, M., Adams, S.E., Andrade, L.J., Yaeger, D., van Schravendijk, M.R., Holt, D.A., Gilman, M., Clackson, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  41. Complementary DNA encoding the human T-cell FK506-binding protein, a peptidylprolyl cis-trans isomerase distinct from cyclophilin. Maki, N., Sekiguchi, F., Nishimaki, J., Miwa, K., Hayano, T., Takahashi, N., Suzuki, M. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
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